Different mechanisms of hydroxyl radical production susceptible to purine P2 receptor antagonists between carbon monoxide poisoning and exogenous ATP in rat striatum

摘要

Previous studies have suggested that carbon monoxide (CO) poisoning stimulates cAMP production via purine P2Y11-like receptors in the rat striatum, activating cAMP signaling pathways, resulting in hydroxyl radical ((OH)-O-center dot) production. Extracellular ATP was thought likely to trigger the cascade, but the present study has failed to demonstrate a clear increase in the extracellular ATP due to CO poisoning. The CO-induced (OH)-O-center dot production was attenuated by the P2Y11 receptor antagonist NF157, in parallel with its abilities to suppress the CO-induced cAMP production. The (OH)-O-center dot production was more strongly suppressed by a non-selective P2 receptor antagonist, PPADS, which had no effect on cAMP production. More selective antagonists toward the respective P2 receptors susceptible to PPADS, including NF279, had little or no effect on the CO-induced (OH)-O-center dot production. The intrastriatal administration of exogenous ATP dose-dependently stimulated (OH)-O-center dot production, which was dose-dependently antagonized by PPADS and NF279 but not by NF157. Exogenous GTP and CTP dose-dependently stimulated (OH)-O-center dot production, though less potently. The GTP-induced (OH)-O-center dot production was susceptible to both of NF279 and PPADS, but the CTP-induced (OH)-O-center dot production was resistant to PPADS. The mechanism of (OH)-O-center dot production may differ between CO poisoning and exogenous ATP, while multiple P2 receptors could participate in (OH)-O-center dot production. The CO-induced (OH)-O-center dot production was susceptible to the inhibition of NADPH oxidase, but not xanthine oxidase. Also, the NADPH oxidase inhibition suppressed (OH)-O-center dot production induced by forskolin, a stimulator of intracellular cAMP formation. It is likely that (OH)-O-center dot is produced by NADPH oxidase activation via cAMP signaling pathways during CO poisoning.